PROJECT SUMMARY Surface modifications of compliant vascular graft biomaterials hold promise for the improved treatment of cardiovascular disease. Rigid synthetic materials have been implanted successfully as large diameter vascular grafts or cardiac devices; yet, patients with these devices are often required to take life-long anticoagulant pharmacologic therapies. The primary reasons for vascular graft failure are the mismatched mechanical properties (stiff grafts sewn into elastic arteries), thrombosis (due to poor blood contacting properties), and the lack of in situ endothelialization. In the development of surface modified compliant vascular grafts there have been few studies to determine the mechanisms of thrombosis, intimal hyperplasia, and in situ endothelialization. Our goal is therefore to use poly(vinyl) alcohol (PVA) biomaterials to determine the necessary success criteria for a vascular graft implant. By modulating the mechanical properties (compliance) and surface topography and examining the graft thrombosis, endothelialization, and implant intimal hyperplasia, we will define the necessary guidelines for vascular graft biomaterials. These guidelines may be applicable to numerous blood-contacting devices, which require non-thrombogenic surfaces capable of supporting rapid endothelial cell migration in vivo. To achieve this goal, the proposed studies will employ topographical modifications to the luminal surface of PVA biomaterials with variable compliance properties. PVA is a biocompatible material, which due to the tunable material properties can attain mechanical properties equivalent to native arteries as well as a large range above and below native values. By methodically changing the compliance values and examining outcomes, we will determine the desired properties and property tolerances that can be translated to any vascular graft biomaterial. The addition of surface modifications to the PVA vascular grafts has the potential to improve in vivo endothelial cell coverage, while maintaining a non- thrombogenic surface. The proposed studies will employ luminal topographical modifications to increase endothelial cell migration and maintain cell functions, while preventing smooth muscle cell migration and proliferation, both of which will protect against thrombosis and improve vascular healing. By systematically changing and examining the mechanical and luminal surface properties of the PVA biomaterials, we will determine how the modifications affect: 1) thrombus formation in native, non-anticoagulated blood under physiologic ex vivo flow conditions; 2) endothelial cell attachment, migration, and function, specifically the reduction of endothelial cell markers of thrombosis and inflammation; and 3) vascular healing and in situ endothelialization after surgical placement in clinically relevant animal models. Our team of experts is uniquely positioned to develop and study the design criteria needed for blood-contacting biomaterials. The results of the proposed studies will define the critical tolerances for graft compliance and surface properties which can be applied to cardiovascular biomaterials and devices.